PDF(Pubmed)
Abstract：
Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.
摘要：
不确定潜能（CHIP）的克隆造血源于造血祖细胞中与衰老相关的获得性突变，显示克隆扩增并产生表型改变的白细胞。我们将CHIP-DNMT3A突变与4,946名社区居住的成年人中牙周炎和牙龈炎症的患病率更高相关联。要对DNMT3A驱动的芯片进行建模，我们使用具有杂合功能缺失突变R878H的小鼠，相当于人类热点突变R882H。用Dnmt3aR878H/骨髓（BM）细胞部分移植导致突变细胞克隆扩增成髓系和淋巴系，并在周围的BM和破骨细胞巨噬细胞中增加了破骨细胞前体的丰度。DNMT3A驱动的受体小鼠的克隆造血促进了自然发生的牙周炎，并加重了实验诱导的牙周炎和关节炎，与破骨细胞生成增强相关，IL-17依赖性炎症和中性粒细胞反应，以及调节性T细胞免疫抑制活性受损。DNMT3A驱动的克隆造血和，随后,雷帕霉素治疗可以抑制牙周炎。DNMT3A驱动的CHIP代表了一种可治疗的不良造血状态，可促进炎症性骨丢失。
